Safety, PK/PD, and anti-tumor activity of RO6874281, an engineered variant of interleukin-2 (IL-2v) targeted to tumor-associated fibroblasts via binding to fibroblast activation protein (FAP).

Abstract

e15155 Background: High-dose (HD) IL-2 is approved for patients with melanoma and renal cell carcinoma but is associated with significant toxicity, given only in an inpatient setting. RO6874281 is a novel, monomeric, bispecific IL-2v immunocytokine that completely lacks binding to IL-2Rα, retains IL-2Rβγ binding, and shows pM binding affinity to FAP on tumor-associated fibroblasts. While the IL-2v domain activates IL-2R expressing immune effector CD8 T and NK cells independent of FAP-binding, targeting via FAP results in retention of IL-2v within tumors in order to selectively promote immune responses within the tumor microenvironment. Methods: Study BP29842 investigated safety, PK/PD and anti-tumor activity of RO6874281. Multiple ascending doses ranging from 5mg to 35mg were given weekly i.v. in an outpatient setting to 35 patients with metastatic solid tumors. Results: Most frequent adverse events ( > 30%) were pyrexia, infusion related reactions, fatigue/asthenia, nausea, diarrhea, decreased appetite and elevated aspartate and/or alanine transaminase. The majority of events were mild or moderate (Grade 1/2). The maximum tolerated dose was declared at 20mg, using one-step intra-patient escalation (15mg followed by 20mg). Preliminary PK analysis indicated a non-linear elimination profile typical of target mediated drug disposition. Single safe doses of RO6874281 yielded > 6 fold higher exposures than those achieved with a full cycle of conventional HD IL-2. As expected from abolished IL-2Rα binding, RO6874281 rapidly expands effector T and NK cells but not Tregs, both in peripheral blood and tumors. Objective long-lasting ( > 6 months) responses were observed in one patient each with head and neck cancer, penile squamous cell carcinoma and checkpoint inhibitor resistant malignant melanoma across the tested dose range. Conclusions: RO6874281 is the first targeted IL-2 variant with acceptable outpatient safety to display monotherapy activity including in tumor types not previously reported to respond to IL-2. Ph1b/Ph2 studies in combination with atezolizumab and other agents are currently underway. Clinical trial information: NCT02627274.